Glucokinase (sometimes to be abbreviated as “GK” in the present specification) (EC2.7.1.1) is one of the 4 kinds of hexokinases found in mammals, and is also called hexokinase IV. GK is an enzyme that catalyzes conversion of glucose to glucose 6-phosphate, which is the first step of the glycolytic system. GK is mainly present in pancreatic β cell and the liver. In pancreatic β cell, it functions as a sensor of extracellular glucose concentration that defines glucose stimulated insulin secretion, and in the liver, enzyme reaction of GK becomes a rate determinant, which controls glycogen synthesis and glycolysis. The three hexokinases (I, II and III) other than GK show the maximum enzyme activity at a glucose concentration of 1 mM or below, whereas GK shows low affinity for glucose and a Km value of 8-15 mM, which is close to the physiological blood glucose level. Therefore, intracellular glucose metabolism is promoted via GK, which corresponds to the changes in the blood glucose level from normal blood glucose (5 mM) to postprandial blood glucose (10-15 mM).
The hypothesis proposed by Matschinsky et al in 1984, “GK functions as a glucose sensor in pancreatic β cell and hepatocyte” has been demonstrated through analysis of glucokinase genetically-engineered mouse in recent years (see non-patent documents 1-5). That is, GK hetero-deficient mouse showed hyperglycemia state, and further, disordered insulin secretion reaction caused by stimulation with sugar. GK homo-deficient mouse dies soon after birth showing remarkable hyperglycemia and urinary sugar. On the other hand, GK overexpression mouse (hetero type) showed decreased blood glucose level, increased blood glucose clearance rate, increased liver glycogen content and the like. From these findings, it has been clarified that GK plays a key role in the systemic glucose homeostasis. In other words, when GK activity decreases, insufficient insulin secretion and lower liver glucose metabolism occur, which in turn causes the onset of impaired glucose tolerance or diabetes. Conversely, increased GK activity due to the activation or overexpression of GK promotes insulin secretion and liver glucose metabolism, which in turn increases systemic sugar utilization to improve glucose tolerance.
In addition, GK gene abnormality has been reported mainly in the family of Maturity Onset Diabetes of the Young called MODY2, and analysis thereof has clarified that GK functions as a glucose sensor and plays an important role in glucose homeostasis also in human (see non-patent document 6). In GK gene abnormality, due to the decreased affinity of GK for glucose (increased Km value) and decreased Vmax, the blood glucose threshold value of insulin secretion increases and the insulin secretory capacity decreases. In the liver, due to the decreased GK activity, decreased glucose uptake, promoted gluconeogenesis, decreased glycogen synthesis and liver insulin resistance are observed. On the other hand, a family with a mutation increasing the GK activity has also been found. In such family, fasting hypoglycemia associated with increased plasma insulin concentration is observed (see non-patent document 7).
As mentioned above, GK acts as a glucose sensor in mammals including human, and plays an important role in blood glucose regulation. On the other hand, control of blood glucose utilizing the glucose sensor system of GK is considered to open a new way of treating diabetes in many type 2 diabetes patients. Particularly, since a GK activating substance is expected to show insulin secretagogue action in the pancreatic β cell and glucose uptake promotion and glucose release suppressive action in the liver, such substance will be useful as a prophylactic or therapeutic drug for type 2 diabetes.
In recent years, it has been clarified that pancreatic p cell type glucokinase expresses locally in the feeding center (Ventromedial Hypothalamus: VMH) of rat brain. A subset of nerve cell present in VMH is called glucose responsive neuron, and plays an important role in the body weight control. From electrophysiological experiments, the neuron is activated in response to physiological changes in the glucose concentration (5-20 mM). However, since the glucose concentration sensor system of VHM is assumed to have a mechanism mediated by glucokinase as in the case of insulin secretion in the pancreatic β cell, different from pancreatic β cell and the liver, a medicament capable of activating glucokinase of VHM has a possibility of providing not only a blood glucose corrective effect but also improvement of obesity.
As mentioned above, a medicament having a GK activating action is useful as a prophylactic or therapeutic drug for diabetes or diabetes chronic complications such as retinopathy, nephropathy, neurosis, ischemic cardiac diseases, arteriosclerosis and the like, and further as a prophylactic or therapeutic drug for obesity.
As nitrogen-containing 5-membered heterocyclic compounds, the following compounds have been reported. However, none of the compounds has been reported to show a glucokinase activation.
Patent document 1 (WO2006/062972) discloses that a compound represented by
wherein R8 is phenyl substituted by 0 to 5 particular substituents, and the like; R8a is H or C1-4 alkyl; and
is a nitrogen-containing 5- or 6-membered heteroaryl, is a selective inhibitor of serine protease and useful for a thrombus obstructive disease and the like. In this reference, the following compound is disclosed.

Non-patent document 8 (Chemical Abstract Registry No.: 303791-54-0) discloses the following compound.

Non-patent document 9 (Journal of Organic Chemistry (2005), 70(18), 7243-7251) discloses the following compounds.

Non-patent document 10 (Heterocycles (2005), 65(4), 797-808) discloses the following compound.

Patent document 2 (JP2002-296739) discloses the following compound.

Patent document 3 (WO2000/27823) discloses the following compound.

Non-patent document 11 (Angewandte Chemie, International Edition (2000), 39(6), 1115-1117) discloses the following compound.

Non-patent document 12 (Tetrahedron (1998), 54(8), 1407-1424) discloses the following compound.

Non-patent document 13 (Inorganic Chemistry (1997), 36(22), 5135-5137) discloses the following compounds.

Patent document 4 (JP05-155882) discloses the following compounds.

Non-patent document 14 (Journal of the Chemical Society, Chemical Communications (1993), (3), 243-5) discloses the following compounds.

Non-patent document 15 (Tetrahedron (1992), 48(30), 6231-44) discloses the following compound.

Non-patent document 16 (Journal of Medicinal Chemistry (1981), 24(5), 639-43) discloses the following compound.

Patent document 5 (U.S. Pat. No. 4,218,457) discloses the following compound.

Non-patent document 17 (NIPPON KAGAKU KAISHI (1975), (2), 334-8) discloses the following compound.

Patent document 6 (U.S. Pat. No. 3,256,288) discloses the following compound.

Patent document 7 (U.S. Pat. No. 3,354,173) discloses the following compounds.

Non-patent document 18 (Journal of Medicinal Chemistry (1965), 8(2), 220-3) discloses the following compound.

Non-patent document 19 (Chemical Abstract Registry No.: 930508-86-4) discloses the following compound.

Non-patent document 20 (Chemical Abstract Registry No.: 746594-95-6) discloses the following compound.

Non-patent document 21 (Chemical Abstract Registry No.: 438019-51-3) discloses the following compound.

Non-patent document 22 (Chemical Abstract Registry No.: 438018-38-3) discloses the following compound.

Non-patent document 23 (Chemical Abstract Registry No.: 779297-46-0)) discloses the following compound.

Non-patent document 24 (Chemical Abstract Registry No.: 730926-85-9) discloses the following compound.
    patent document 1: WO2006/062972    patent document 2: JP-A-2002-296739    patent document 3: WO2000/27823    patent document 4: JP-A-05-155882    patent document 5: U.S. Pat. No. 4,218,457    patent document 6: U.S. Pat. No. 3,256,288    patent document 7: U.S. Pat. No. 3,354,173    non-patent document 1: J. Biol. Chem. 1995, vol. 270, pp. 30253-30256    non-patent document 2: J. Biol. Chem. 1997, vol. 272, pp. 22564-22569    non-patent document 3: J. Biol. Chem. 1997, vol. 272, pp. 22570-22575    non-patent document 4: Japan Clinical, 2002, vol. 60, pp. 523-534    non-patent document 5: Cell 1995, vol. 83, pp. 69-78    non-patent document 6: Nature 1992, vol. 356, pp. 721-722 page    non-patent document 7: New England Journal Medicine 1998, vol. 338, pp. 226-230    non-patent document 8: Chemical Abstract Registry No.: 303791-54-0    non-patent document 9: Journal of Organic Chemistry (2005), 70(18), 7243-7251    non-patent document 10: Heterocycles (2005), 65(4), 797-808    non-patent document 11: Angewandte Chemie, International Edition (2000), 39(6), 1115-1117    non-patent document 12: Tetrahedron (1998), 54(8), 1407-1424    non-patent document 13: Inorganic Chemistry (1997), 36(22),    non-patent document 14: Journal of the Chemical Society, Chemical Communications (1993), (3), 243-5    non-patent document 15: Tetrahedron (1992), 48(30), 6231-44)    non-patent document 16: Journal of Medicinal Chemistry (1981), 24(5), 639-43    non-patent document 17: NIPPON KAGAKU KAISHI (1975), (2), 334-8    non-patent document 18: Journal of Medicinal Chemistry (1965), 8(2), 220-3    non-patent document 19: Chemical Abstract Registry No.: 930508-86-4    non-patent document 20: Chemical Abstract Registry No.: 746594-95-6    non-patent document 21: Chemical Abstract Registry No.: 438019-51-3    non-patent document 22: Chemical Abstract Registry No.: 438018-38-3    non-patent document 23: Chemical Abstract Registry No.: 779297-46-0    non-patent document 24: Chemical Abstract Registry No.: 730926-85-9